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1 Department of Medical Physiology, Panum Institute, and 2 Danish Aerospace Medical Center of Research, Rigshospitalet, University of Copenhagen, DK-2200 Copenhagen; and 3 Department of Medical Biology, University of Southern Denmark, DK-5000 Odense, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Body fluid homeostasis was investigated during chronic bed rest (BR) and compared with that of acute supine conditions. The hypothesis was tested that 6° head-down BR leads to hypovolemia, which activates antinatriuretic mechanisms so that the renal responses to standardized saline loading are attenuated. Isotonic (20 ml/kg body wt) and hypertonic (2.5%, 7.2 ml/kg body wt) infusions were performed in eight subjects over 20 min following 7 and 10 days, respectively, of BR during constant sodium intake (200 meq/day). BR decreased body weight (83.0 ± 4.8 to 81.8 ± 4.4 kg) and increased plasma osmolality (285.9 ± 0.6 to 288.5 ± 0.9 mosmol/kgH2O, P < 0.05). Plasma ANG II doubled (4.2 ± 1.2 to 8.8 ± 1.8 pg/ml), whereas other endocrine variables decreased: plasma atrial natriuretic peptide (42 ± 3 to 24 ± 3 pg/ml), urinary urodilatin excretion rate (4.5 ± 0.3 to 3.2 ± 0.1 pg/min), and plasma vasopressin (1.7 ± 0.3 to 0.8 ± 0.2 pg/ml, P < 0.05). During BR, the natriuretic response to the isotonic saline infusion was augmented (39 ± 8 vs. 18 ± 6 meq sodium/350 min), whereas the response to hypertonic saline was unaltered (32 ± 8 vs. 29 ± 5 meq/350 min, P < 0.05). In conclusion, BR elicits antinatriuretic endocrine signals, but it does not attenuate the renal natriuretic response to saline stimuli in men; on the contrary, the response to isotonic saline is augmented.
vasopressin; atrial natriuretic factor; urodilatin; natriuresis; angiotensin II
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE OPERATION OF THE VOLUME homeostatic mechanisms is sensitive to changes in posture. In the upright-seated position, normal subjects exhibit a low stable renal sodium output for at least 14 h (17). Transition from the seated position to head-down tilted bed rest (BR) promptly increases urine flow and sodium excretion (28). In the supine position, a progressive increase in sodium excretion is observed at least during the daytime (1, 8). It is understandable, therefore, that in humans during prolonged supine or head-down BR, sodium and fluid balances are negative (14). Within 24 h of BR, a new steady state occurs with sustained reductions of plasma and extracellular fluid volume, total body water, and body weight (7, 13, 18). Plasma renin activity and aldosterone concentration are increased (5, 14), whereas plasma norepinephrine concentration is reduced or unchanged (7, 15, 18). It is, however, still uncertain how atrial natriuretic peptide (ANP), arginine vasopressin (AVP), ANG II, and urodilatin adapt to several days of BR.
When exposed to weightlessness in space, humans appear to adapt to a state of fluid and sodium reduction compared with being supine on the ground (26). After 4-6 days of flight, antinatriuretic mechanisms are activated and the renal response to an isotonic saline load is attenuated. It is the general assumption that the fluid-deficient state during weightlessness or BR is induced by an initial redistribution of blood and fluid from the caudad to the cephalad portions of the body leading to central hypervolemia. This increases the wall tension of the heart and the adjacent venous vessels and is supposed to establish a natriuresis and diuresis through neuroendocrine reflexes. Subsequently, in combination with a decreased food and fluid intake, a new equilibrium is reached with a reduction of extracellular and intravascular volumes.
Because intravascular volume is reduced during prolonged head-down BR (7, 13, 18), it might be anticipated that the renal responses to a saline load would be attenuated compared with acute supine conditions as found by Mauran et al. (23) after 3 days of BR. Drummer et al. (9), however, performed infusions of isotonic saline before and after 6 days of head-down BR and observed that the renal excretion rates of sodium and water were, in fact, indistinguishable. Judging from these reports, it appears that during extended BR, renal responsiveness to volume expansion is regained despite intravascular volume contraction. If so, this restoration of the renal responses to a volume stimulus indicates that the human body adapts to a new state, where central blood volume is kept at a level below that of the acute horizontal supine position. Thus it appears that during chronic horizontal or head-down BR or during weightlessness in space, the regulation of renal sodium and water excretion is adjusted to operate around a set point with regard to central and intravascular volume that is closer to that of the upright than the supine position.
The mechanisms by which a fluid-deficient state is maintained during prolonged BR are not defined at present. We, therefore, tested the hypothesis that following several days of BR, fluid and sodium deficits lead to activation of the antidiuretic and antinatriuretic endocrine mechanisms (e.g., vasopressin and the renin-angiotensin-aldosterone system) and to suppression of natriuretic peptides (e.g., ANP and urodilatin), so that the renal responses to saline stimuli are attenuated. We used a 10-day, 6° head-down BR protocol including control of the intake of sodium (200 meq/24 h). The acute supine position was selected as the control position, and noninfusion control experiments were conducted to achieve a more comprehensive understanding of the adaptation of volume homeostatic mechanisms to BR.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Eight male subjects aged 22-27 yr (weight 69.8-104.6 kg, mean 83.0 kg; height 178-192 cm, mean 185 cm) participated in the experiment. Women were not investigated due to practical reasons and because other background investigations were made in men (26). However, in a recent study, human gender did not influence the cardiovascular and renal responses to water immersion (30). All subjects had a negative history of cardiovascular and kidney diseases and were healthy as indicated by a physical examination and normal hemoglobin, creatinine, and electrolyte concentrations. The protocol was approved by the regional scientific ethical committee of Copenhagen, Denmark (j.no. KF 01-320/94), and the subjects gave their written informed consent.
Protocol. The study included two different regimes: 1) 10-day supine BR in a bed tilted 6° head down (BR), and 2) acute supine horizontal BR (Sup; 6 h). Each subject was investigated three times during each regimen: 1) a time control experiment on day 6; 2) an isotonic saline load (0.9% saline, 20 ml/kg body wt) on day 7 (Iso); and 3) a hypertonic saline load (2.5% saline, 7.2 ml/kg body wt) on day 10 (Hyper). The order of Sup vs. BR experiments was randomized. When Sup was performed after BR, the two investigations were separated by at least 5 wk.
The subjects received a fixed diet containing 200 meq sodium/day from days 1 to 10 during BR and for 3 days before each study day under the Sup protocol. In this period, they were instructed to avoid strenuous physical activity and to abstain from smoking, alcohol, and caffeine-containing drinks. During Sup, the subjects spent the night in the laboratory before each investigation. During BR, the subjects spent all 10 days at the laboratory and were only allowed to get out of bed for a maximum of 15 min each morning for personal hygiene and during the day for going to the toilet. During the infusion experiments, they stood up only for voiding. Urine was collected on 24-h basis before each study day for estimation of the sodium excretion. Mean arterial pressure and heart rate were measured four times every day at 7 AM and 1, 6, and 11 PM.Infusion protocol.
The subjects were awakened at 7 AM. After the subjects emptied their
bladders, a standardized meal, consisting of 400 ml of tap water and
one slice of bread with jam, was ingested. Thereafter, they remained
supine except during voiding. Venous cannulas were placed in both
cubital veins for infusions and for withdrawal of blood. Three hours
after the subjects awakened, a 20-min infusion of either isotonic
saline (0.9% saline, 20 ml/kg body wt) or hypertonic saline (2.5%
saline, 7.2 ml/kg body wt) or a time control (without infusion) was
performed. The infusions were performed manually by inflation of a
cuff-pressure system (26). Urine was sampled four times by
emptying the bladder in the upright position 30 min before and 50, 110, and 170 min after the start of infusion for measurement of urine volume
and osmolality and concentrations of sodium, potassium, and urodilatin.
Three venous blood samples of 17 ml each were obtained 50 min before
and 25 and 100 min after the start of infusion. Blood for measurement
of plasma osmolality and plasma concentrations of sodium, potassium,
and protein were sampled in heparinized tubes. Blood for determination
of plasma concentrations of ANG II, ANP, and AVP was obtained in
precooled polyethylene tubes containing EDTA and aprotinine (Novo
Nordisk, Bagsvaerd, Denmark). The samples were centrifuged immediately at 4°C, and plasma was stored at 
18°C until extraction.
Analyses. Osmolality in plasma and urine was measured by freezing-point depression (Advanced osmometer 030, Advanced Instruments). Sodium and potassium concentrations in plasma and urine were measured by flame photometry (IL243, Instrument Laboratory). Plasma concentrations of protein were measured by the biuret method (16). The plasma concentrations of ANP, ANG II, and AVP and urine concentrations of urodilatin were measured by radioimmunoassays. All plasma and urine samples were acidified with acetic acid, and the peptides were extracted by use of C18 Sep-Pak cartridges (Waters, Millipore, Bedford, MA) as previously described (10). ANG II immunoreactivity was determined by use of a specific antibody (produced by P. Christensen) using a procedure described previously (20). Cross-reactivity with ANG I was <0.2%. The detection limit was 1.4 pg/ml, and the extraction recovery of unlabeled ANG II was 94%. The intra-assay variation coefficient at an ANG II concentration of 40 pg/ml was 7%. ANP immunoreactivity was determined using an antibody purchased from Peninsula Laboratories (Merseyside, UK) using of a procedure previously described (29). The intra-assay variation coefficient at an ANP concentration of 20 pg/ml was ~5%. The extraction recovery of unlabeled ANP was 60%. AVP immunoreactivity was determined by use of a specific antibody [kindly provided by Dr. J. Warberg (21)] according to a procedure described by Emmeluth et al. (11). There was negligible cross-reactivity with oxytocin, vasotocin, and ANG II. The detection limit was <0.2 pg/ml. The extraction recovery of unlabeled AVP added to plasma was 87%. Intra-assay variation coefficient was 8% at an AVP concentration of 1.2 pg/ml. The urodilatin immunoreactivity in urine was determined by a specific antibody (S1969, Biomedica, Vienna, Austria) as previously described (6). Cross-reactivity with hANP(99-126), hANP(4-28), rANP, endothelin-1, AVP, and ANG II was <0.001%. Detection limit was 0.6 pg/ml for urine, and extraction recovery of unlabeled urodilatin was 90%. Intra-assay coefficients of variation were 21% with a concentration of 6 pg/ml of urine and 8% with a concentration of 22 pg/ml of urine. Results of radioimmunoassays were not corrected for incomplete recovery.
Statistical analysis. Results are means ± SE. Data were subjected to a two-way analysis of variance for repeated measures within series and between series. In case of P < 0.05, the differences between baseline and infusion periods and the differences among control, isotonic, and hypertonic series and the differences between Sup and BR experiments were evaluated systematically by Newman-Keuls test. P < 0.05 was considered to indicate significance. In case of apparent variance in homogeneity, the data were subjected to logarithmic transformation before statistical evaluation.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Adaptation to BR.
Body weight declined significantly already from day 1 (Table
1) as expected (14).
Accordingly, fluid balance was negative and sodium excretion was
elevated during the first days of BR, indicating loss of sodium and
body water (Table 1). However, immediately before the infusion
experiments, neither the mean 24-h urine flows nor the sodium excretion
rates were significantly different (Table 1). At this time also, mean
baseline urine flows, i.e., the mean value of the 2-h baseline periods
of the three interventions in Sup and BR (Sup 1.5 ± 0.2 and BR
1.5 ± 0.1 ml/min), and mean sodium excretion rates (Sup 99 ± 13 and BR 96 ± 14 µmol/min) were identical. Therefore, it
can be assumed that a steady state was achieved from day 6.
Mean baseline potassium excretions (Sup 41 ± 5 and BR 101 ± 12 µmol/min) were increased during BR compatible with catabolism,
e.g., of muscle tissue during BR. Baseline free water clearance
(CH2O) was lower during BR than during Sup experiments (Sup
0.7 ± 0.2 and BR 1.3 ± 0.2 ml/min). The mean baseline
urodilatin excretion rates (Sup 4.5 ± 0.3 and BR 3.2 ± 0.1 pg/min) and plasma ANP concentrations (Sup 42 ± 3 and BR 24 ± 3 pg/ml) were lower during BR than during Sup experiments. Baseline
plasma osmolality was higher during BR (Sup 285.9 ± 0.6 and BR
288.5 ± 0.9 mosmol/kgH2O), but, unexpectedly, mean
baseline plasma AVP concentrations were reduced by ~50% (Sup
1.7 ± 0.3 and BR 0.8 ± 0.2 pg/ml). Mean baseline plasma ANG
II concentrations were doubled during BR compared with Sup (Sup
4.2 ± 1.2 and BR 8.8 ± 1.8 pg/ml). On day
10 of BR, plasma sodium concentration was 1-2 meq/l lower
than in the Sup experiments (Table 2).
Mean arterial pressures and heart rates were unchanged during the 10 days of BR (Table 1).
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Isotonic load: effects of BR.
The urine flow rates increased in response to isotonic infusions during
both conditions as expected (Sup 1.3 ± 0.1 to 3.6 ± 0.5 and
BR 1.6 ± 0.2 to 4.7 ± 0.9 ml/min). However, the
diuretic effect of the infusions, measured as the excess urine flow
above that of the respective control experiments, was larger during BR
than in the Sup experiments (Sup 183 ± 94 and BR 509 ± 127 ml/350 min, P < 0.057; Table
3). Sodium excretion increased equally in
Sup and BR experiments (92 ± 12 to 393 ± 38 and 107 ± 19 to 399 ± 40 µmol/min, respectively; Fig.
1). In the BR time control series,
however, accumulated sodium excretion was significantly lower than
during Sup (Sup 53 ± 4 and BR 40 ± 5 meq/350 min; Table 4). Therefore, the natriuretic effect of
the infusion measured as the accumulated excess sodium excretion above
that of the respective control experiment was significantly increased
during BR (Sup 18 ± 6 and BR 39 ± 8 meq/350 min; Table 3).
The rate of excretion of urodilatin increased in response to isotonic
infusion in both Sup and BR experiments to peak values of 6.7 ± 1.4 and 5.2 ± 1.1 pg/min, respectively (Fig. 1). There was a
tendency toward a lower excretion rate during BR. However, during
saline infusion, the excess urodilatin excretions above those of the
appropriate time control series were not significantly different.
Expectedly, plasma ANP concentrations increased in response to the
isotonic loads (Sup 41 ± 4 to 49 ± 5 and BR 22 ± 3 to
39 ± 4 pg/ml) and plasma ANG II levels decreased (Sup 5.0 ± 1.5 to 2.2 ± 0.5 and BR 9.0 ± 2.4 to 2.5 ± 0.5 pg/ml)
(Fig. 2). Plasma osmolality and AVP concentrations did not change significantly (Fig.
3). Plasma protein concentrations decreased
equally in Sup and BR experiments (Table 2).
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Hypertonic load: effects of BR.
In response to the hypertonic infusions, the urine flow rates increased
equally in the two conditions (Sup 1.3 ± 0.2 to 1.9 ± 0.3 and BR 1.2 ± 0.2 to 1.8 ± 0.1 ml/min; Fig. 1). There was no
significant difference in the accumulated urine flows (Table 4) or the
excess urine flows above time control (Table 3), meaning that the
diuretic responses to hypertonic infusion during Sup and BR were not
different. After the hypertonic infusion, the sodium excretion rate
increased less during BR (Fig. 1), and the accumulated sodium excretion
was lower during BR compared with Sup (Sup 85 ± 6 and BR 69 ± 5 meq/350 min; Table 4). In the corresponding time control series,
however, accumulated sodium excretion was also significantly lower
during BR (Sup 53 ± 4 and BR 40 ± 5 meq/350 min; Table 4).
Therefore, the accumulated excess sodium excretion (above that of the
respective time control) during BR was not significantly different from
Sup (Sup 32 ± 8 and BR 29 ± 5 meq/350 min; Table 3),
demonstrating identical natriuretic responses to hypertonic infusion in
the two conditions. In contrast, the urodilatin excretion rates
increased only in the Sup experiment and peaked at 6.5 ± 0.7 pg/min, i.e., the urodilatin response to hypertonic infusion was
abolished during BR (Fig. 1). The plasma ANP concentrations, however,
increased by 30% in both Sup and BR experiments (Sup 38 ± 2 to
49 ± 5 and BR 22 ± 3 to 30 ± 4 pg/ml), although
baseline levels were significantly different (P < 0.05; Fig. 2). Plasma ANG II concentrations decreased by 60-70%
in both Sup and BR experiments (Sup 3.9 ± 2.0 to 1.7 ± 0.3 and BR 8.5 ± 1.9 to 2.5 ± 0.5 pg/ml; Fig. 2).
Plasma osmolality was elevated during BR and increased in response to
the hypertonic infusions in both situations (Sup 285.9 ± 0.7 to
292.8 and BR 287.9 ± 0.7 to 295.9 ± 1.1 mosmol/kgH2O; Fig. 3). Plasma AVP concentrations, however, were markedly reduced during BR and increased in response to
hypertonic infusions in both Sup and BR experiments (Sup 1.8 ± 0.4 to 2.5 ± 0.3 and BR 0.6 ± 0.3 to 1.7 ± 0.3 pg/ml;
Fig. 3). The relationship between plasma osmolality and plasma
AVP was changed so that the investigated part of the response curve is shifted to the right during BR (Fig. 4).
The estimates of the slopes are almost identical [0.113 vs. 0.126 (pg/ml)/(mosmol/kgH2O); Fig. 4], indicating that the AVP
response to an increase in plasma osmolality was preserved but with a
higher set point during BR, i.e., BR induces a sizable decrease in
osmoreceptor sensitivity.
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Hypertonic vs. isotonic loads. In the Sup experiments, the excess sodium excretions above those of the control series were larger after hypertonic than after isotonic infusion (Iso 18 ± 6 and Hyper 32 ± 8 meq/350 min; Table 3), indicating a concentration-dependent component in the natriuretic response. During BR, this component was absent (Iso 39 ± 8 and Hyper 29 ± 5 meq/350 min). In the Sup experiments, the urodilatin excretion increased equally in response to isotonic and hypertonic infusion to maximal values of 6.7 ± 1.4 and 6.5 ± 0.7 pg/min, respectively (Fig. 1). During BR, the urodilatin excretion rate increased only in response to isotonic infusion, i.e., the urodilatin response to hypertonic infusion was absent during BR.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The hypothesis of chronic hypovolemia developing during BR was supported by the decrease in body weight and the changes in the levels of ANG II, ANP, and urodilatin. Our data show that during BR, 1) antinatriuretic mechanisms are activated, 2) natriuretic mechanisms are attenuated, 3) plasma vasopressin is low despite elevated plasma osmolality, and 4) the natriuretic response to isotonic volume expansion is augmented despite the readjustments of the endocrine parameters in the direction of sodium retention. Taken together, the results indicate that BR leads to hypovolemia and hyperosmolality possibly by changing the set points of diuretic and natriuretic mechanisms.
Adaptation to BR. Confirming the classic hypothesis that central volume expansion leads to a fluid-contracted state (14), we observed that body weight decreased during the first days of BR. Concomitantly, sodium excretion increased and fluid balance was negative. Although not measured, it is, therefore, most likely that within the 6-10 days of BR, central blood volume was reduced to a level below that of the acute supine position and that the associated decrease in the distension of the atria caused a reduction of plasma ANP (22, 29) and an increase in plasma ANG II.
Plasma AVP was low during BR and approximately one-half of the acute supine value. We had expected an increase due to the reduction in central blood volume and the increase in plasma osmolality. Recent studies in humans have indicated that arterial baroreceptors modulate AVP release (24). Kamegai et al. (19) observed that static carotid baroreceptor stimulation by neck suction counteracts the increase in AVP release in response to passive head-up tilting. Therefore, one possible mechanism is that during BR, the suppression of AVP release is caused by the continuous increased mean pressure in the carotid sinus due to the small but prolonged foot-to-head hydrostatic pressure gradient. Another possible mechanism includes BR-induced increase in aortic pulsation. Results of recent work by Norsk et al. (27) indicate that arterial pulse pressure is a codeterminant of AVP release. The change in plasma osmolality may be secondary. The human kidney is very sensitive to vasopressin (2), therefore, lower plasma AVP levels might well have caused the increase in plasma osmolality by increased renal excretion of solute-free water. Urodilatin, a recently discovered renal natriuretic peptide, which is present only in urine, has been suggested to be a possible mediator of renal sodium excretion (8). We observed, with a newly developed assay (6), that BR attenuated average (Sup 4.5 ± 0.3 and BR 3.2 ± 0.1 pg/min, P < 0.05) and accumulated urodilatin excretion rates of urodilatin (Table 4). The attenuation of sodium excretion during BR in the control experiments could, therefore, have been caused by the BR-induced reduction of renal urodilatin synthesis. However, little is known about the physiological regulation of urodilatin synthesis. In summary, BR causes hypovolemia and hyperosmolality associated with elevated ANG II generation and reduced ANP release and urodilatin production. The primary changes seem to include a decrease in plasma AVP that may have been caused by prolonged carotid baroreceptor stimulation induced by the head-down tilted BR. The fluid-contracted state may have been caused by increased renal excretion of solute-free water due to supression of AVP.Isotonic load: effects of BR. Infusion of isotonic saline increases the extracellular fluid and central blood volume without affecting plasma sodium concentration and osmolality. We expected that the renal responses to the volume load would be more pronounced in the acute supine position than after the adaptation to BR, where apparently an intravascular volume reduction had occurred. This was not the case. We observed that the diuretic and natriuretic responses to isotonic saline infusion during Sup and BR were very similar. In addition, because the baseline control excretory rates of sodium and fluid were lower during BR, the renal effects of the saline load were, in fact, augmented. Our results are in accordance with results of an investigation by Drummer et al. (9), who observed that the urine flow and sodium excretory rates in response to an isotonic saline load were unchanged after 6 days of BR. Mauran et al. (23), however, found an attenuated renal response to isotonic sodium loading after 3 days of BR. The different results might be explained by the different degree of hydration because the subjects in the study of Mauran et al. (23) were overhydrated due to oral water loading inducing a very high baseline diuresis. Another explanation could be the different duration of BR, in this case, the discrepancy would suggest that extended BR leads to resetting of volume regulation causing augmented renal responses to volume loading.
The plasma concentrations of AVP were unchanged in response to the isotonic load and therefore cannot provide an explanation for the increase in urine flow. CH2O was negative probably due to the relative fluid-restricted state and the associated levels of vasopressin in plasma. CH2O did not change, therefore, increases in urine flow were generated by changes in the excretion of solutes. Under the assumption that renal sensitivity to AVP was unchanged by BR, the lower baseline levels of AVP may have facilitated the diuretic response to isotonic loading. In response to the isotonic load, the plasma concentrations of ANG II decreased by 73% during BR and by 54% during Sup, indicating that the response of the renin-angiotensin-aldosterone system to a volume stimulus was augmented by BR. It is, therefore, conceivable that the larger natriuretic response to the isotonic load during BR was due to a more pronounced inhibition of the renin-angiotensin-aldosterone axis. In addition, plasma ANP concentrations increased following loading by some 77% during BR and by only 29% during Sup. Therefore, the more pronounced natriuretic response to isotonic infusion during BR could also have been caused by the augmented ANP release. Because urodilatin production was less during BR, this substance probably did not participate in the augmented renal sodium output.Hypertonic load: effects of BR. Despite the smaller volume, the infusion of hypertonic saline is causing an increase in the extracellular fluid volume almost as large as that of the isotonic infusion, due to osmotic drag of fluid from the intracellular to the extracellular space. It can be calculated that in the present experiments, the increase in extracellular volume from the hypertonic load was ~75% of that obtained by isotonic volume expansion. This value fit well with the observed reductions in plasma protein concentrations in response to infusions (Table 2). In addition to volume expansion, the hypertonic infusion also provides an osmotic stimulus, which may have contributed to the natriuretic response (1). We expected that the renal responses to hypertonic saline loading would be more pronounced in the acute supine position than during BR due to relative hypervolemia. This was not the result. We observed that urine flow rates were similar and that sodium excretion rates were slightly attenuated by BR. However, because the excretory rates of sodium also during time control were lower during BR, the natriuretic effect of the hypertonic load was not significantly different from Sup.
Baseline plasma AVP concentrations were suppressed during BR, so it could have been expected that the release of AVP in response to the hypertonic load also was impeded during BR. This was not the case. As indicated by Fig. 4, the relationship between plasma osmolality and plasma concentrations of AVP was changed. The relationship was shifted to the right during BR, but the slopes were almost identical, indicating that the AVP response to an increase in plasma osmolality was preserved but with a lower set point. Thus BR did not affect the sensitivity of AVP release to changes in plasma osmolality. The plasma concentrations of ANG II decreased following hypertonic loading by 71% during BR and by 56% during Sup and to very similar levels. Plasma ANP concentrations increased by 36% during BR and by 20% during Sup. Therefore, the relative responses tended to be more pronounced during BR and similar to those observed after the isotonic load. In response to hypertonic infusion, urodilatin excretion increased only during Sup. Thus BR blunted the urodilatin response to hypertonic loading. The attenuated sodium excretion in response to hypertonic infusion during BR could, therefore, be due to attenuated urodilatin production. It has previously been suggested that urodilatin production is influenced through stimulation of osmoreceptors (12). The present results rather indicate that urodilatin excretion is controlled by volume changes. In accordance with this, Norsk et al. (25) observed that urodilatin excretion increased during central hypervolemia induced by water immersion.Hypertonic vs. isotonic loads. Previous investigations in dogs have demonstrated that the renal sodium excretion was augmented when a saline load was administrated as a hypertonic solution compared with the same salt load administrated as an isotonic solution (12). This exaggerated natriuresis was accompanied by a larger excretion of urodilatin, which was not abolished by blockade of the renin-angiotensin-aldosterone system (11). Studies in humans have, however, generally failed to demonstrate a more pronounced natriuresis following hypertonic saline loading compared with that of isotonic (osmomediated natriuresis) conditions, and it has been hypothesized that the response to a hypertonic saline load in humans is dependent on relative hypervolemia and the rate of the increase in plasma sodium (3, 4). A recent study (1) of saline loading of water-deprived humans suggested that the level of plasma sodium concentration must be relatively high to allow the demonstration of osmomediated natriuresis, i.e., exaggerated natriuresis in response to a sodium load given as a hypertonic compared with an isotonic solution. In support of these findings, we observed in the Sup experiments, where relative central hypervolemia was expected, that the natriuretic response to hypertonic saline loading was augmented compared with that of isotonic. During BR, where central blood volume is expected to be lower compared with Sup, this difference was eliminated concomitant with reduced production of urodilatin and a small but significant reduction of baseline plasma sodium concentration. Our results, therefore, demonstrate in humans that osmomediated natriuresis in response to hypertonic saline loading is demonstrable and that urodilatin is a possible mediator of this response. The presence of osmomediated natriuresis, however, may depend on the degree of central hypervolemia and the level of plasma sodium concentration.
In summary, we have demonstrated that 1) BR causes body weight reduction and hyperosmolality associated with elevated ANG II generation and reduced ANP release and urodilatin production, compatible with a fluid-contracted state, possibly caused by suppression of AVP secretion; 2) BR is associated with an exaggeration of the natriuretic response to isotonic but not hypertonic volume expansion; and 3) osmomediated natriuresis, possibly mediated by urodilatin, could not be demonstrated during BR possibly due to reduction of central blood volume and/or plasma sodium concentration. In conclusion, the BR-induced hypovolemia did not attenuate the natriuretic responses to saline stimuli in men despite activation of ANG II and reduction of ANP and urodilatin release.Perspectives
Head-down BR has often been used as a model for simulating the effects of weightlessness on the cardiovascular and renal systems. During studies of weightlessness, Norsk et al. (26) found an attenuated renal response to isotonic saline loading. This study demonstrates that there is a discrepancy between the renal responses to acute saline loading performed during BR and during weightlessness. Therefore, BR may be less suitable for simulation of the effects of weightlessness on body fluid regulation. Other simulation models such as long-term water immersion appear more attractive, and the possibility of even better methods should be explored. BR leads to resetting of volume regulation, and the natriuretic response to the hypertonic load apparently depends on the magnitude of central blood volume. Further studies, however, are required to explain the reason for the low vasopressin level during BR and to define the possible mediators of the natriuretic response to osmostimulation. The importance of urodilatin and other humoral factors should be further investigated.| |
ACKNOWLEDGEMENTS |
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The authors thank P. Kjeldgaard, I. H. Pedersen, B. Sorensen, B. L. Christensen, T. Eidsvold, and S. K. Hansen for expert technical assistance. R. Videbaek and K. Holmsgaard, Clinic of Aviation Medicine, University of Copenhagen, are acknowledged for providing appropriate research facilities.
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FOOTNOTES |
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The study was supported by the Danish Research Counsils (Grant 9602455) and the Danish Heart Foundation.
Address for reprint requests and other correspondence: M. H. Bestle, Dept. of Anesthesia and Intensive Care, Gentofte Hospital, Univ. of Copenhagen, DK-2900 Hellerup, Denmark (E-mail: mbestle{at}dadlnet.dk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 15 September 2000; accepted in final form 28 February 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
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, Supine (Sup);
, head-down bed rest (BR). Values are means ± SE;
n = 8. *Significant deviations from baseline (B)
(P < 0.05). §Significant deviations from
Sup at same time (P < 0.05).
